Curcumin, Curcumin Nanoparticles and Curcumin Nanospheres: A Review on Their Pharmacodynamics Based on Monogastric Farm Animal, Poultry and Fish Nutrition

Nanotechnology is an emerging field of science that is widely used in medical sciences. However, it has limited uses in monogastric farm animal as well as fish and poultry nutrition. There are some works that have been done on curcumin and curcumin nanoparticles as pharmaceutics in animal nutrition. However, studies have shown that ingestion of curcumin or curcumin nanoparticles does not benefit the animal health much due to their lower bioavailability, which may result because of low absorption, quick metabolism and speedy elimination of curcumin from the animal body. For these reasons, advanced formulations of curcumin are needed. Curcumin nanospheres is a newly evolved field of nanobiotechnology which may have beneficial effects in terms of growth increment, anti-microbial, anti-inflammatory and neuroprotective effects on animal and fish health by means of nanosphere forms that are biodegradable and biocompatible. Thus, this review aims to highlight the potential application of curcumin, curcumin nanoparticles and curcumin nanospheres in the field of monogastric farm animal, poultry and fish nutrition. We do believe that the review provides the perceptual vision for the future development of curcumin, curcumin nanoparticles and curcumin nanospheres and their applications in monogastric farm animal, poultry and fish nutrition.


Introduction
Biotechnology and nanotechnology are considered as the 21st century's most emerging and advanced technologies. The term nanotechnology was first coined by Norio Taniguchi in 1974 [1]. Nanotechnology (from the Latin nanus, meaning the dwarf) can be defined as the understanding, design, development and application of materials and devices whose least functional makeup is on a nanometer scale (~1 to 100 nm) or one billionth of a meter (10 −9 ) [2]. In brief, nanotechnology deals with the conversion of larger molecules to nanometer size and it changes the physico-chemical nature of the cell matrix in terms of human or animal welfare. The changes may occur based on solubility, absorption, the transporting system, excretion and antagonistic behavior of the nanomaterials [3]. Nanobiotechnology can be an indispensable tool to monitor the individual cell development at the individual molecule level [4]. Nevertheless, one of the most important and extensive uses of nanobiotechnology is the area of human medicine [5], where it provides nanomaterials with the controlled drug delivery system for cancer remediation [6], nutrient utilization [7], hormonal controls [8] and gene therapy [9]. In case of animal welfare, the technology can be utilized to improve growth [10,11] and meat quality [11], reproductive performance [12,13], immunity enhancement [14] as well as disease resistance [10], antioxidant activity [15][16][17], and intestinal function [16] including Pharmaceutics 2020, 12 food preservation [18]. Nanomaterials can be classified into four categories: metals, polymers, natural compounds and nanostructured materials [19]. Metals are usually mineral nanoparticles such as gold [20], copper [21], selenium [22], palladium [23] etc. However, the main problem of using metal nanomaterial is its non-biodegradability [19]. Polymers of nanomaterials are pieces of nanometer-sized polymers which are biodegradable and biocompatible and can be utilized very well [24]. The biocompatibility is the most important concern in nanobiotechnology in order to have low or no toxic effects on the organism [25][26][27][28]. Nanoparticles that come from natural sources are known as natural compounds (natural polymers or proteins) which are highly biodegradable, biocompatible and distributable in the body [19]. Nanostructured materials are the conjugations of lipid or protein with nanoparticles such as phospholipid-based nanoparticles (curcumin nanospheres) or phosphoprotein-based nanoparticles (casein micelles). From a nutritional point of view, natural and nanostructured nanoparticles have great advantages in terms of nutrient delivery by means of encapsulation or adhesion of the nanomaterials. However, natural or nanostructured nanoparticles may be toxic in high doses if they are not properly adjusted in the organisms. In animal nutrition, nanotechnology has been discussed regarding the nature of food and its taste, texture, processing time, thermal susceptibility, stability, safety and bioavailability of nutrients as well as the feeding of animals [29]. Nutrients can be delivered in the form of nanoparticles or in aided forms such as nanocapsules and emulsifications as well as nanosphere forms.
In recent years, phytogenic natural compounds are widely used in animal feeds as antimicrobial growth promoters (AGPs) to replace the antibiotics in monogastric animal [30,31], poultry [11] or aquaculture [32] feed since the indiscriminate use of antibiotics in animal feed may favor the emergence of antibiotic-resistant strains of bacteria [11] and their accumulation in edible tissues [33]. In fact, the European Union (EU) has already banned AGPs in animal feeds, and the Food and Drug Administration (FDA) of the USA is going to restrict the use of AGPs in animal feeds [34,35]. For animal disease resistance and growth enhancement, currently researchers are putting emphasis on the use of natural growth promoters and non-antibiotic growth promoters (NGPs) in terms of improvement of the gastrointestinal tract (GIT) through the incorporation of various feed additives, for example, curcumin and its derivatives which have antimicrobial, antioxidant, anti-inflammatory, appetite increasing, immune-modulatory and gastroprotectve effects on animal health [11].
Turmeric (Curcuma longa L.), a tropical rhizomatous herb of the Zingiberaceae family, is regarded as the "golden spice", used as curry powder in South and South-East Asian cuisine [11,36]. Turmeric has a medicinal value in human and animal health [37]. The dried turmeric rhizome consists of 3-6% terpenes and terpenoids, 6-8% protein, 6-10% fat, 60-70% carbohydrate and 3-6% fiber [38]. Curcumin or diferuloylmethane [1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione] is a hydrophobic and polyphenolic compound extracted from the perennial herb, Curcuma longa [39][40][41]. Curcumin, is a yellow pigment, found in turmeric at 3-6% with bioactive properties [37]. The melting point of curcumin ranges from 176 to 177 • C [42]. Commercial curcumin usually has 77% diferuloylmethane, 17% dimethoxy-curcumin and 6% bisdemethoxycurcumin [43]. Curcumin has a relatively low toxicity and is generally regarded as safe (GRAS) which defined as the chemical or substance added to food is considered as safe by experts, and so is exempted from the usual Federal Food, Drug, and Cosmetics Act food additive tolerance requirements by the United States Food and Drug Administration (FDA) [44]. For many years, curcumin has been used in Indian ayurvedic remedies and Chinese medicines [44,45]. Despite the beneficial effects of curcumin, it has some limitations such as low water solubility (hydrophobic), an unstable chemical structure, being rapidly metabolized but poorly absorbed in the body as well as its utilization or bioavailability differing depending on the species and sex [41]. Likewise, Wahlstrom and Blennow [46] reported that oral administration of curcumin (1 g/kg) to rats resulted in a huge excretion of curcumin (about 75%) in the feces with a small amount in the urine and blood plasma. However, Patil et al. [47] postulated that the piperine in black pepper could enhance the bioavailability of curcumin by 20-fold and CYP3A4 in cytochrome P450, p-Glycoprotein and uridine

Curcumin or Nanocurcumin in Monogastric Farm Animal, Poultry and Fish Nutrition
Indiscriminate use of antibiotics in monogastric farm animal and poultry farming as well as in aquaculture has caused the emergence of new pathogenic strains. These consequences have warranted the development of safe and alternative growth promoters and immunity enhancers in farm animal, poultry and fish production. Monogastric farm animals like swine, poultry and fish are usually reared in intensive production systems which may ultimately affect their health status through different types of diseases and secondary infections and ultimately reduce their production

Curcumin or Nanocurcumin in Monogastric Farm Animal, Poultry and Fish Nutrition
Indiscriminate use of antibiotics in monogastric farm animal and poultry farming as well as in aquaculture has caused the emergence of new pathogenic strains. These consequences have warranted the development of safe and alternative growth promoters and immunity enhancers in farm animal, poultry and fish production. Monogastric farm animals like swine, poultry and fish are usually reared in intensive production systems which may ultimately affect their health status through different types of diseases and secondary infections and ultimately reduce their production performance [72][73][74][75][76]. Use of phytogenic additives in animal, bird and fish feed is a centuries-old practice. With vast potential areas of application, nanotechnology is still in its infancy for animal feed and nutritional studies [4]. The most common health-enhancing prophylaxis is nutritional strengthening of the gastrointestinal system in animals [77]. In this section we discuss the use of curcumin or turmeric (as the source of curcumin), and nanocurcumin based on the nutritional aspects related to the growth, reproductive capacity, digestibility, stress response, immune functions and histopathology as well as disease distance in different age stages of swine, rabbit, poultry and fish (Tables 1-4).

Dietary Turmeric/Curcumin in Swine Nutrition
In swine, the weanling period is the most crucial time from a nutritional perspective because at this stage young piglets are quickly shifted from sow's milk to a dry-and low-digestible-starch-based diet which may ultimately affect their digestive and immune systems and finally cause morbidity or mortality in pigs [78]. The consequences may be due to distinctive changes in gastrointestinal tract (GIT) architecture, changes in autochthonous bacteria in the gut which deteriorate the small-intestinal barrier function and absorption of potential nutrients [79,80]. In the weanling period, low feed intake and feed efficiency, body weight loss and diarrhea are common phenomena in piglets. In farm levels, nearly 50% growth retardation may occur at the weaning stage of pigs [80]. To overcome this problem and to increase the post-weaning growth of pigs, farmers usually depend on some commercial antibiotics in the diets of the weanling pigs. However, the indiscriminate use of therapeutic antibiotics in farm animals may create the development of antibiotic-resistant strains of bacteria which may be harmful for the animal as well as the consumers in turn. Different countries of the world are now thinking to minimize or completely eliminate the inclusion of antibiotics in the diet for farm animals. To increase the production and health status of pigs, it is imperative to find out the alternatives to antibiotics which can be used either singly or in combination that are able to overcome stunted growth as well as the problems in the digestive system of weanling pigs. Different dietary components depending on their solubility, digestibility, viscous-forming ability and acid-buffering ability can potentiate or stimulate the gut health of pigs by preventing proliferation of pathogenic bacteria [78]. In this regard, dietary turmeric or curcumin have shown their positive effects in swine nutrition [31,68,69,[81][82][83][84][85][86]. Maneewan et al. [81] reported that dietary turmeric can induce nutrient digestibility, blood parameters and intestinal gut health in nursery piglets when they offered 0.10% and 0.20% turmeric in the diets. In another reports, Liu [82,83] postulated that dietary turmeric oleoresin or in combination with capsicum oleoresin and garlic botanical could enhance the weight gain and gut mucosa health by alleviating diarrhea and reducing inflammation caused by E. coli bacteria. Dietary curcumin extracted from the turmeric rhizome also proved its promising effects as an immune stimulant in weaned piglets. As an antibiotic replacer and potential additive, dietary curcumin at 300 or 400 mg/kg of diet has shown its effectiveness in replacing quinocetone by means of enhancing growth performance, jejunal mucosal barrier integrity in the intestine and stimulating the immune system of weaned piglets challenged with enterotoxigenic E. coli [31]. But, Ilsley et al. [84] reported that dietary curcumin (200 mg/kg) had no effect on the growth and immune system of weaned piglets in relation to quillaja saponin. Intrauterine growth retardation (IUGR) which is defined as the growth below the 10th percentile for gestational age, has adverse effects on animals as demonstrated in pigs in terms of stunted growth, fatty liver and insulin resistance [68,69]. However, these conditions can be attenuated by the supplementation of curcumin in the diets of IUGR piglets. In addition, dietary supplementation Pharmaceutics 2020, 12, 447 5 of 23 of curcumin at 200 mg/kg can alleviate the jejunum damage through the Nrf2/Keap1 pathway in the intestine of IUGR growing pigs. Curcumin with other phytogenic additives such as resveratrol has shown combined effects in replacing dietary antibiotics in pigs. Resveratrol, like curcumin, has potential anti-inflammatory, bacteria-regulating and immune-promoting effects [85]. In a study, dietary curcumin (300 mg/kg) in combination with resveratrol (300 mg/kg) showed regulatory effects on gut microbiota, down-regulating the Toll-like-receptor 4 mRNA (TLR4) signaling pathway, reducing the intestinal pathology and enhancing the immunity by secreting immunoglobulin in weaned piglets.

Dietary Turmeric/Curcumin in Poultry Nutrition
As the world human population is increasing, the demand for poultry meat also increasing. In poultry industry, birds are usually raise in extremely crowded condition which causes poor hygiene and stunted growth in chickens. To solve this problem, the antibiotics are extensively use to enhance chicks growth and health status. Due to the abuse of antibiotics and antimicrobial resistance matter, some phytogenic compounds especially turmeric or curcumin could be used to reduce the overwhelming dependence on antibiotics as well as increase the production performance of poultry industry [73]. A numerous studies have been conducted on the efficacy of turmeric or curcumin in poultry nutrition. In poultry industry, necrotic enteritis (NE) and avian coccidiosis are commons among the most important infectious diseases which resulted extensive mortality and substantive economic losses world-wide [87]. In a study, Lee et al. [87] demonstrated that dietary supplementation of turmeric oleoresin (4 mg/kg) and capsicum oleoresin (4 mg/kg) extracts could enhance the growth performance, reduce the gut lesions as well as serum levels of Clostridium perfringens (etiological agent of NE) toxins which resulted from molecular and cellular immune changes and finally showed their resistance against avian NE. In addition, dietary turmeric powder (TP) in single (7 g/kg) or in combination with neem and vitamin E have shown to increase growth, hematology, body composition, meat quality and serum biochemical parameters in broiler chicken [88,89]. However, Qasem et al. [90] reported that dietary turmeric powder (20 g/kg) did not improve the growth and immunity in broiler chickens. In case of Wenchang broiler chickens, dietary turmeric extract (100 to 300 mg/kg) could enhance the growth performance, breast muscle content and reduce the fat content in abdomen of chicks [91]. Moreover, Akhavan-Salamat et al. [92] demonstrated that dietary turmeric rhizome powder (TRP) or betaine (Bet) alone or in combination could improve the hematology and immune responses Pharmaceutics 2020, 12, 447 7 of 23 but TRP is more effective than Bet in terms of tolerance to heat stress in male Ross chicks. In laying hens, dietary TP showed no effects on body or egg weight and production at higher level (4% TP/kg), however, low level of TP (2% TP/kg) could increase egg production and quality slightly in Hisex laying hens [93]. Mirbod et al. [94] reported that increasing dietary turmeric or Curcuma longa rhizome powder (CRP) could enhance the egg quality in terms of improving egg shell thickness and hardness but abating cholesterol level in egg yolk in Leghorn laying hens. Nowadays, quail raising is getting much attention to meet the protein demand in addition to chickens. Dietary turmeric has shown its positive effects in quail rearing [12,95,96]. Turmeric (0.5%) with exogenous commercial enzyme, Panzyme (0.1%) has proven to increase growth performance and immune status in Japanese quail. Furthermore, dietary supplementation of turmeric in parent stock of Japanese quail may increase the egg quality in terms of higher vitellogenin, high density lipoprotein (HDL), vitamin A, B12, white egg protein and decrease the low density lipoprotein (LDL), total fat contents in eggs, in addition, increase the carcass content and antioxidant activity in female offsprings.
Nevertheless, curcumin extracted from turmeric has beneficial effects on poultry nutrition. Curcumin and turmerones extracted from lipophilic turmeric have shown their combined effect on the increment of growth, antioxidant and antimicrobial activities in broiler chickens [11]. Kim et al. [97] reported that dietary curcumin can be coccidiosis resistant challenged with Eimeria by means increasing body weight, and reducing fecal oocysts, gut lesions as well as increasing body immunity in Ross broiler chickens. On the other hand, Galli et al. [14,66] demonstrated curcumin (30 and 50 mg/kg) alone can reduce the lipid peroxidation and increase the antioxidant level in eggs of laying hens or curcumin combined with microencapsulated phytogenics (carvacrol, thymol and cinnamaldehyde improve the growth, flesh quality and unsaturated fatty acids in broiler chicks. Curcuminoids (222 mg/kg) in feeds showed protective effects on aflatoxin B1 (1 mg/kg) toxicity in male Ross broiler chicks [15] or curcuminoids (60 mg/kg) with tuna oil could increase the breast fillet and inhibit the auto-oxidation in thigh meat in slow growing chickens [98]. Rajput et al. [99,100] reported that supplementation of curcumin at 200 mg/kg can improve the growth, fat metabolism and intestinal integrity, whereas; curcumin (150 mg/kg) with lutein (150 mg/kg) could enhance the freshness of meat and antioxidant capacity in Arbor Acres broiler chickens. In addition, dietary curcumin alone (50 and 100 mg/kg) could improve the meat quality and oxidant stability in muscle as well as activate the glutathione (GSH) related enzymes and detoxify the Nrf2-mediated phase II detoxifying enzyme systems in broiler chickens [17,101,102]. Xie et al. [65] explained that curcumin has important role in reducing fat deposition in abdomen by decreasing liver and blood lipid contents, and lipogenic gene expressions. Thermal or temperature and feed-borne aflatoxin B1 (AFB1) effects are the most crucial events in poultry industry. The supplementation of dietary curcumin can attenuate the AFB1 toxicity and resistance to heat stress in broiler and laying hens in terms of different attributes such as growth increment, as well as inhibition of hepatoxicity, CYP2A6 enzyme-mediated bioactivation of AFB1, enhancement antioxidant biomarkers, blood chemistry and immune related gene expressions [103][104][105][106]. In case of Japanese quail, Sahin et al. [107] reported that high ambient temperature (34 • C) causes oxidative stress in quail, however, dietary curcumin supplementation (200 or 400 mg/kg) could ameliorate the problem by increasing body weight, feed intake and reducing serum malondialdehyde (MDA) and heat shock protein 70 (HSP70) as well as modulating Nrf2/HO-1 pathway in quail. Ruan et al. [16,108] postulated that supplementation of curcumin (200 to 800 mg/kg) could enhance the growth, serum GSH, jujunal mucosa and villus surface in intestine and reduce MDA, interleukin-1β, tumor necrosis factor-α as well as detoxify ochratoxin A-related gene expressions in ducklings.
Use of curcumin nanoparticle or nanocurcumin in animal nutrition is a very recent event. In poultry nutrition, Rahmani et al. [10,109] reported that male broiler chicks (Ross 308) had decreased weight gain and high feed conversion ratio, and increased blood partial pressure of carbon dioxide (pCO 2 ) and hematocrit at cold temperature (13-15 • C), however, when the chicks were offered feed with curcumin or nanocurcumin, the body weight and villus surface in intestine increased but MDA and caecal Escherichia coli decreased in broiler chicken at cold stressed condition. In another report, Marchiori et al. [12] Pharmaceutics 2020, 12,447 8 of 23 demonstrated that thermal stress in quail negatively affects performance, however, dietary curcumin (30 mg/kg) and nanoencapsulated curcumin (10 mg/kg) could effectively enhance the quail health in terms of performance production, egg quality like antioxidant capacity of egg yolk, reduce feed conversion, lower thiobarbituric acid reactive substances (TBARS) and higher monounsaturated fatty acids (MUFA) in egg yolk of quail at cold stress condition (1 to 17 • C). Interestingly, in this experiment, dose of nanoencapsulated curcumin (10 mg/kg) was three time lesser than free curcumin (30 mg/kg) which showed potential effect using nanotechnological tool.    1-day-old male broiler chickens/ 12-weeks of trial Total 120 chicks in four diet groups: a 2 × 2 factorial design was used where the main factors included adding aflatoxin B1, AFB1 (< 5 vs. 100 µg/kg) and curcumin, CM (0 vs. 150 mg/kg) in a corn/soybean-based diet ↑ liver injury, ALT, AST, MDA, but ↓ albumin, total protein, CAT, GSH, GSH-Px and induced AFBO-DNA in AFB1 fed; these attributes are lowered, prevented or protected by CM added diets [104] 1-day-old male Arbor Acres broiler chickens/ 28-days of trial Total 120 chicks in six diet groups: control group, curcumin alone-treated group (450 mg/kg feed), the group fed AFB1-contaminated feed (5 mg/kg feed) plus the low (150 mg), medium (300 mg) or high (450 mg) of curcumin, and the group fed AFB1-contaminated diet alone (5 mg/kg feed) ↓ liver weight and toxicity, ↑ body weight in curcumin treated groups; ↑ mRNA, protein expressions and CYP2A6 enzyme activity in AFB1-fed group; however, ↓ mRNA, protein expressions and CYP2A6 enzyme activity on dose dependent manner in curcumin fed [105] 22-weeks-old Roman laying hens/ 21-days of trial Total 336 laying hens in 3 diet groups: first group as a thermoneutral control (25 • C), second group at high temp (32 • C, 6 h/day), given a basal diet, third group was five treatment groups (100, 150, 200, 250, 300 mg/kg curcumin) (H1, H2, H3, H4, H5, respectively) fed a basal diet under high temp conditions (32 • C, 6 h/day) ↑ SOD at H2 and H3 fed diets; ↑ total antioxidant capacity at H2, H3 and H5 fed diets; ↑ CAT and GSH-Px at H3 diet; ↓ MDA in curcumin added diets; ↑ CAT, SOD, GSH-Px and T-AOC in liver, heart and lungs of curcumin treated groups compared with heat stressed control group [106] 10-days-old Japanese quails/ 42-days of trial Total 180 birds reared at either 22 • C (thermoneutral) or 34 • C (heat stress) for 8 h/day (0900-1700) until the age of 42 days. Birds in both environments were randomly fed 1 of 3 diets: basal diet and basal diet added with 0, 200 or 400 mg of curcumin per kg of diet.
↑ BW, FI, and ↓ FE, MDA, nuclear factor, HSP70 in response to increasing supplemental curcumin level in the diets [107] 1-day-old White Pekin ducklings/ 21-days of trial Total 540 mixed-sex birds in three dietary treatments: controls (fed only the basal diet), a group fed an OTA-contaminated diet (2 mg/kg feed), and a group fed the same OTA-feed plus 400 mg/kg of curcumin ↑ BW, ADG, and no enterotoxicity in curcumin fed diet compared to OTA diet; ↓ interleukin-1β, tumor necrosis factor-α, MDA, apoptotic gene expression, mt-transcription factors and ↑ GSH, jejunal mucosa, tight junction protein in curcumin fed diets than OTA diet [16] 1-day-old male Cherry Valley Pekin ducklings/ 21-days of trial Total 720 male ducklings in four dietary treatments: control group were fed a basal diet and the remainder were fed the basal diet supplemented with 200, 400, or 800 mg/kg curcumin ↑ jejunal and hepatic curcumin contents with 400 and 800 mg/kg; ↑ SOD1, CAT, GST, GPX1, HO-1, MRP6, CYP1A4, CYP2D17, Nrf2 transcript, ABCB1 and ↓ CYP1B1, CYP2A6 expressions in jejunal mucosa in curcumin fed diets; [108]

Dietary Turmeric and Curcumin in Rabbit Nutrition
Rabbit has a great importance like poultry as well as a high delicacy as a human food. However, rabbits are also very much prone to coccidiosis which is the most common digestive disease in rabbits. Due to coccidiosis, huge intestinal damage can occur in rabbits which may cause reduced body weight and nutrient-absorption capacity. As an endoparasite, Eimeria spp. is the most prevalent in the digestive system of farm rabbits [30]. There are few research works which have been conducted on dietary turmeric or curcumin in rabbit ailments [30,110]. Cervantes-Valencia et al. [30], for the first time, reported on the use of dietary curcumin as a natural anticoccidial alternative in adult rabbits. The results showed the positive effect of aqueous extract of curcumin on the excretion of oocysts of Eimeria spp. in New Zealand white rabbits such as reducing the number of oocysts and their concentration of eggs per gram of feces at the dose of 40 mg curcumin /kg body weight. However, Basavaraj et al. [110] found no beneficial effects of dietary turmeric rhizome powder (TRP) either at 0.15% or at 0.30% in the diets on blood biochemical and meat characteristics of broiler rabbits reared under summer stress conditions.

Dietary Turmeric and Curcumin in Fish Nutrition
Aquaculture is considered as one of the fastest growing food producing sectors world-wide, serving a vital role in mitigating the problem of animal-protein demand, especially in the third-world countries [75]. In comparison to farm animals or poultry, fish is a better source of high quality protein, micronutrients (vitamins and minerals) and essential fatty acids, especially polyunsaturated fatty acids (linoleic acid, LA; α-linolenic acid, ALA; eicosapentaenoic acid, EPA; docosahexaenoic acid, DHA; and arachidonic acid, ARA) [72,111]. However, due to the rapid horizontal and vertical expansion of aquaculture as well as a land shortage problem, most of aquaculture is practiced under intensive and stressful farming system which causes emerging and infectious disease outbreaks [112]. In this regard, fish farmers mostly use antibiotics and chemicals to enhance the fish health status and productivity. However, unauthorized and extensive use of antibiotics in aquaculture may lead to the emergence of antibiotic-resistant bacteria which results in environmental hazards, bacteriological changes and accumulation of antibiotic residuals in fish tissues that have public health concerns [33]. To overcome the problem of unethical use of antibiotics in aquaculture, many researchers have proposed the use of herbal medicines, especially turmeric or curcumin, as antibiotic replacers in the aquaculture industry (Table 4). In a very recent report, Rajabiesterabadi [113] postulated that dietary turmeric at 10 mg/kg could ameliorate the harmful effect of copper in terms of enhancing the antioxidant parameters such as superoxide dismutase (SOD), lysozyme, catalase (CAT), glutathione peroxidase (GSH-Px) and bactericidal activity, as well as decreasing liver cytokine's gene expressions such as tumor necrosis factor-alpha (TNF-α) and interleukins like IL1-b and IL10 in common carp. Dietary curcumin (2%) can also enhance the growth and hematological values, and antioxidant as well as immune responses in rainbow trout challenged with Aeromonas salmonicida subsp. achromogenes [114]. Baldissera et al. [63] reported that a 100% disease resistance against Streptococcus agalactiae in silver catfish with high appetite can be achieved when fish were offered dietary curcumin (150 mg/kg). Tilapia is one of the most cultured fish species in the world. However, there is also disease problems and health issues in tilapia aquaculture. Mahmud et al. [64] demonstrated that dietary curcumin supplementation (50 or 100 mg/kg diet) can improve the growth (increased final weight, daily weight gain, specific growth rate), feed utilization (low feed conversion ratio, high protein efficiency ratio), antioxidant status (high catalase, and low GSH and MDA activities), immune responses (increased lysozyme activity, total immunoglobulins like IgG and IgM levels) as well as disease resistance in tilapia challenged with A. hydrophila. Likewise, some other studies reported that dietary curcumin supplementation in percentage inclusion (0.5%, 1% or 2%) or amount inclusion in the diet (100-200 mg/kg) could enhance the growth, feed efficiency, hematology, glycogenesis, serum total protein and bactericidal activity, liver heat shock protein and disease resistance against Vibrio alginolyticus in Nile tilapia [32,115,116]. Furthermore, El-Barbary et al. [117,118] postulated that tilapia fish with intraperitoneal injection of AFB1 (6 mg/kg body weight) can be ameliorated by dietary garlic which showed better performance than curcumin, however, the combination of garlic and curcumin (10 mg/kg) had more benefits than high concentrations (20 mg/kg) of garlic or curcumin against aflatoxicosis. In case of freshwater climbing perch fish (Anabas testudineus), Manju et al. [119][120][121] explained that dietary curcumin (0.5% or 1%) or curcumin analogue as salicylcurcumin (0.5%) have protective effects against lipid peroxidation and DNA damage as well as increase the growth, survival rate and disease resistance in A. testudineus. Dietary curcumin can enhance the liver health status in fish. In a study, curcumin supplementation (0.5% and 1%) showed the hepatoprotective effects in Jian carp on carbon tetrachloride (CCl 4 )-induced liver damage (low aspartate transaminase (AST), alanine transaminase (ALT), hepatocyte degeneration, MDA in liver) in terms of enhanced antioxidative activities (SOD, antioxidant capacity, GSH in liver) and inhibiting related cytokine expressions (TNF-α, IL-1β) via the NF-kB signaling pathway [122]. Jiang et al. [123] reported that crucian carp offered with dietary curcumin (5 mg/kg) could improve the growth (increase final weight, feed efficiency, hepatopancreas weight), digestibility (high trypsin and lipase activities), gastrointestinal (GIT) antioxidant activities (high SOD, CAT, glutathione reductase (GR), GSH, GSH-Px, glutathione-S-transferase (GST) activities) and upregulation of GIT-related mRNA gene expressions (trypsin, lipase, Na + , K + -ATPase (NKA), alkaline phosphatase (AKP), gamma-glutamyl transpeptidase (γGT), creatine kinase (CK), SOD1, CAT, GSH-Px, GST, and GR genes). To date, there has been no research work conducted on curcumin nanoparticles in fish nutrition and most of the studies dealt with the extremely high dosage of curcumin in fish which seemed to be effective. However, for the sense of cost-effective and more scientific usage, we need to minimize the amount of curcumin in fish feed as an alternative to antibiotics. Therefore, it is imperative to find out correct nanoformulations of curcumin in aquafeeds to produce disease-free fish and a higher production of the aquaculture species.

Curcumin Nanospheres in Monogastric Farm Animal, Poultry and Fish Nutrition
Natural products especially from plant sources always have a significant and promising role in pharmaceutics discovery in terms of therapeutic effects and biological properties. Curcumin as a natural therapeutic agent consists of two symmetric o-methoxy phenolic groups attached to α and β -unsaturated β-diketone which have potential as photophysical and photochemical properties [124].
Priyadarsini [58] reported that β-diketone groups can chelate ions with formation of curcumin-metal complexes and reduce metal toxicity in living organisms. However, due to the poor solubility, poor pharmacokinetic profile and lack of proper bioavailability problems, it is needed to improve and find out a more efficient way to deliver the curcumin nanoparticles in a site-specific manner with highest bioavailability. In this regard, nanotechnological incorporation of curcumin using different nanocarriers may enhance efficacy and ensure a targeted and sustained release of curcumin [125]. Moreover, curcumin has great potential as natural pigment which may increase the feed intake in animals and due to its antioxidant properties it can produce quality and healthy animals for human consumption, which is particularly important [126]. Eight types of nanocarriers have been proposed which can be used in nanobiotechnology as smart drug delivery systems (SDDSs) (Figure 2): carbon nanotubes, dendrimers, micelles, liposomes, super paramagnetic iron oxide nanoparticles (SPION), gold nanoparticles, quantum dot and mesoporous silica nanoparticles (MSN) [127]. In vitro and in vivo studies recommend that nanocurcumin loaded with a nanocarrier has more health-span-promoting factors than traditional or native curcumin where water solubility and bioavailability of curcumin can be significantly improved through nanoencapsulation with lipid, polymeric nanoparticles, nanogels and dendrimers, and conjugating to metal oxide nanoparticles [125]. nanotubes, dendrimers, micelles, liposomes, super paramagnetic iron oxide nanoparticles (SPION), gold nanoparticles, quantum dot and mesoporous silica nanoparticles (MSN) [127]. In vitro and in vivo studies recommend that nanocurcumin loaded with a nanocarrier has more health-spanpromoting factors than traditional or native curcumin where water solubility and bioavailability of curcumin can be significantly improved through nanoencapsulation with lipid, polymeric nanoparticles, nanogels and dendrimers, and conjugating to metal oxide nanoparticles [125]. The effectiveness of nanodelivery systems depend on the mode of loading and release of pharmaceutic agents, long life-span as well as high therapeutic efficiency with minimum side-effects [48]. Recently, our research group developed a nanosphere loaded with curcumin which indicates curcumin nanosphere is a functional agent that can manipulate pathogenic and Gram-negative bacterium, Vibrio vulnificus in GIT cell deaths [128]. This concept can be further utilized in gastroenteritis diseases in animals to reduce the overwhelming dependence on antibiotics. In addition, Suwannateep et al. [129] reported that mucoadhesive curcumin nanospheres showed 48-49% of The effectiveness of nanodelivery systems depend on the mode of loading and release of pharmaceutic agents, long life-span as well as high therapeutic efficiency with minimum side-effects [48]. Recently, our research group developed a nanosphere loaded with curcumin which indicates curcumin nanosphere is a functional agent that can manipulate pathogenic and Gram-negative bacterium, Vibrio vulnificus in GIT cell deaths [128]. This concept can be further utilized in gastro-enteritis diseases in animals to reduce the overwhelming dependence on antibiotics. In addition, Suwannateep et al. [129] reported that mucoadhesive curcumin nanospheres showed 48-49% of curcumin loading and easy adherence to stomach mucosa as well as release of curcumin in blood circulation of mice model. The application of curcumin nanoparticles with a nanocarrier is not seen yet in animal nutrition or nutritional diseases, as most of the works are related to therapeutic application in human diseases, especially in Alzheimer's disease in which curcumin pigments exhibit unique charge and bonding characteristics that facilitate penetration into the blood-brain barrier and polymerization of β-amyloid in terms of anti-Alzheimer activity [130,131], neurodegenerative disease in central nervous system or skin cancers in the form of polymer-curcumin conjugate micelles, eucalyptol microemulsions, selenium nanoparticles encapsulated PLGA nanospheres with curcumin, nanosuspension-based curcumin etc. [132][133][134][135][136]. Dende et al. [137] reported that nanocurcumin is superior to native curcumin in preventing degenerative changes in terms of cerebral malaria in mice. The experimental study showed that a nanoformulated curcumin (PLGA-curcumin) has better therapeutic index than native curcumin in preventing the onset of neurological symptoms and delaying the death of mice in experimental cerebral malaria. The result of the experiment revealed that a single oral dose of 5 mg PLGA-curcumin containing 350µg of curcumin resulted in 3-to 4-fold higher concentration and prolonged presence of curcumin in the brain than that obtained with 5mg of native curcumin, indicating better bioavailability and more effective nature of PLGA-curcumin. Recently, Baldissera and his group [71,138,139] reported the potential effect of dietary nerolidol nanospheres at 0.5 or 1.0 mL/kg diet in Nile tilapia. The results demonstrated that nerolidol nanospheres supplementation improved the growth, survival, antioxidant activities and fillet fatty acids profile and attenuated/reduced hepatic cellular damage, impaired bioenergetics, microbial contents and neuronal damage as well as disease resistance against the pathogenic Gram-negative bacterium, Streptococcus agalactiae in Nile tilapia. For the first time, the studies showed the benefits of nanobiotechnology in terms of fish health and meat quality as well as the field of animal nutrition. In another study, the same group of researchers have shown that the dietary curcumin-loaded nanocapsule, Eudragit L-100 polymer, enhanced the anti-inflammatory and antioxidant capacity in dairy sheep, where the doses were 10 times lower than the free curcumin [69]. There was no evidence to report the effects of nanospheres or curcumin nanosphere in monogastric farm animal or poultry nutrition.

Conclusions and Future Outlook
During the last decades, people have witnessed the immense popularity of nanotechnology and the potential improvement of phytogenic drugs in terms of their encapsulation to protect from enzymatic degradation, increase solubility, minimize toxicity, act on target basis with prolonged and controlled release, change the mode of pharmacokinetics and the pharmacodynamics of plant-based pharmaceutics and their overall application for mankind. Curcumin and its derivatives have potential with antioxidant, anti-inflammatory, and antimicrobial actions in applied animal science. It has safe, non-toxic and inexpensive but outstanding functional properties which make it more attractive to researchers in comparison to other phytogenic compounds. However, research works are still going on as it has some limitations due to its lipophilic and hydrophobic nature. So, there will be a great scope to use nanotechnological tools for the advancement of curcumin research in animal science. Furthermore, even though curcumin nanoparticles decrease the doses of curcumin, the nanocurcumin form may be toxic and limited in its target delivery system. Therefore, it is imperative to study the toxicokinetics of nanocurcumin in order to minimize the nanocurcumin toxicity as well as effectively deliver the curcumin in target organs of animals. From the perspective of animal nutritional biotechnology, curcumin can be more efficiently utilized using different nanocarriers especially in nanospheric form which may help to ensure effective and target-based controlled release of curcumin in different animal organs. These approaches will be helpful to improve the growth and reproductive health status, immune responses and disease resistance in terms of understanding the digestion, metabolism, immune and excretion pathways of monogastric farm animals, poultry and fishes in a more scientific way as well as to replace antibiotics on farm levels.

Conflicts of Interest:
The authors declare no conflict of interest.